In immunocompetent individuals, non-typhoidal Salmonella serotypes (NTS) are associated with gastroenteritis, a localized infection with low mortality manifesting as diarrhea, vomiting and intestinal cramping. However, in immunocompromised individuals, a breach of mucosal barrier functions can result in the development of a life threatening bacteremia. The incidence of disseminated NTS infections has reached epidemic status in sub-Saharan Africa, where these infections are associated with bacteremia, meningitis and sepsis, and often have a fatal outcome. In young children, epidemiologic studies have determined that severe malaria is an important immunocompromising condition predisposing to NTS bacteremia. In children with severe Plasmodium falciparum malaria the prevalence of disseminated NTS infections is particularly striking. However, the immune defects caused by severe malaria that increase the risk of developing NTS bacteremia, are not known. The objective of this application is to use our recently developed murine co-infection model of malaria and NTS to identify effects of malaria on the immune response to a subsequent bacterial infection. Our central hypothesis is that in pediatric patients, underlying malaria parasite infection leads to both a breach in intestinal barrier function and a reduced ability to check growth at systemic sites by interfering with neutrophil recruitment and bacteriocidal activity. We will test our hypothesis by (i) identifying mechanisms by which underlying malaria parasite infection compromises mucosal inflammation, and (ii) determining effects of malaria parasite infection on immunologic mechanisms that control bacterial organ loads. The fact that NTS/malaria co-infections are understudied, even though they represent a major cause of mortality in sub-Saharan Africa, makes the proposed work highly significant. We expect that the proposed research will provide important and novel insights into specific immune mechanisms that are important for mucosal barrier function to NTS infection. Further, the results of our proposed studies are likely to provide novel paradigms of how polymicrobial infections affect disease outcome. PUBLIC HEALTH RELEVANCE: Nontyphoidal Salmonella serotypes (NTS), which usually cause diarrheal disease in immunocompetent individuals, are a leading cause of bacteremia in immunocompromised individuals in Sub-Saharan Africa. Severe malarial anemia is a major risk factor in African children for dissemination of NTS from the intestine to the bloodstream. We expect that our proposed research to identify the immune defects in pediatric malaria patients predisposing them to NTS bacteremia will provide important new insights into specific immune mechanisms that are important for maintaining the intestinal barrier function to bacteria and broaden our understanding of how simultaneous infection with multiple pathogens affect disease outcome.